Ergotamine Research Paper

Ergotamine, are older drugs still appropriate in modern clinical use?

Ergotamine, now used as a treatment for acute headaches, has medical history spanning several centuries, with mentions regarding its application in obstetrician practice from early 19th century. Ergotamine belongs to a family of ergot alkaloids, derived from ergot fungi, most notably the Claviceps purpurea fungus. This parasitic fungus grows on rye and other grain crops and the ergot alkaloids it produces can cause poisoning, called ergotism, in humans and animals. The symptoms of this poisoning reveal a lot about ergotamine pharmacology. Ergotism is usually associated with dry gangrene and a variety of adverse central nervous system effects such as spasms.
Ergotamine mode
of action is highly complex and involves interaction with several receptors, including: 5-HT (serotonin), dopamine and noradrenaline receptors. In therapeutic concentrations (generally low), ergotamine is a non-specific α-adrenoreceptor agonist, significant 5-HT1B/5-HT1D agonist (at higher doses non-specific 5-HT receptor agonism) and dopamine D2 receptor agonist.
The most significant effect of ergotamine is vasoconstriction, especially large arteries and less so arterioles, and can significantly constrict coronary, pulmonary and cerebral arteries specifically.
This is likely the effect of α-adrenoreceptor and 5-HT1B receptor agonism. The reason ergotamine was used in obstetrician practice was its potent uterotonic action, potentiating uterine contractions, thus help with childbirth, and its vasoconstrictive effect helps prevent post-partum bleeding. This practice is long discontinued as ergotamine has a potential to cause foetal damage, thus pregnancy is considered to be a contraindication. Therapeutic effects of ergotamine, which are the basis for headache treatment, are intracranial vasoconstriction via 5-HT1B receptor interaction and dural plasma extravasation inhibition, trigeminovascular pathway inhibition via the activation of 5-HT1D receptor. These actions best reduce the neurovascular event of migraines when they are long lasting non-frequent
ones.
Ergotamine is available in several forms and more often than not compounded with caffeine, as it helps with absorption.
It exists in an aerosol form, useful for quick uptake into blood. Oral form, while the most common vector, exposes ergotamine to liver metabolism (in this case not entirely understood, yet high rate of first pass metabolism) and thus results in very low bioavailability, <1% of intravenous bioavailability. Ergotamine is also available in suppository form, with comparative bioavailability of 1-3%.
Clinical trials of ergotamine have raised a fair amount of controversy, as the drug has been in use long before proper clinical trial programmes were in place, the number of studies is very limited, methodology of some criticised, and the results contrary one to another. Studies of use of ergotamine as abortive treatment immediately upon onset of a migraine attack fall short of making a solid argument and quantify ergotamine efficacy. While it was superior to placebo in some trials in others it was worse. Overall, consensus is hard to reach on the dosage and efficacy of oral
ergotamine.
This issue, when considered with the amount and severity of side effects caused by the non-specific receptor interaction of ergotamine, and low bioavailability of most common formulations, is a cause for concern and disagreement regarding the place of ergotamine use in a clinical setting. Ergotamine use can cause nausea and vomiting, symptoms already present in patients with migraines. Through increased vagal activity and a reduction of overall sympathetic action it can cause bradycardia, coronary vasoconstriction with ischaemic pain, and in the periphery, vascular stasis increasing the risk of thrombosis, gangrene, coronary vasospasms. With its many cardiovascular effects, contraindications must be closely observed, they include any sort of cardiovascular disease, pregnancy or breastfeeding, impaired hepatic or renal function.
In conclusion, the potential for harm with improper dosing, many side effects enabled by ergotamine non-specificity, difficulties with drug administration and liver metabolism, unclear efficacy and lack of proper clinical trials, contraindications are all arguments against their clinical use. Yet, their mode of action against migraine, 5HT interaction similar to triptans (more specific), could allow ergotamine or other ergot alkaloids to become precursors for more modern approach of drug development. A closer look at ergot alkaloid structure, the function related to it, could be the first step to a new class of drugs, rivalling current migraine medication.